CN107405350A - A kind of pharmaceutical composition containing pyridopyrimidines derivatives or its officinal salt - Google Patents
A kind of pharmaceutical composition containing pyridopyrimidines derivatives or its officinal salt Download PDFInfo
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- CN107405350A CN107405350A CN201780000891.2A CN201780000891A CN107405350A CN 107405350 A CN107405350 A CN 107405350A CN 201780000891 A CN201780000891 A CN 201780000891A CN 107405350 A CN107405350 A CN 107405350A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
The invention discloses a kind of pharmaceutical composition containing pyridopyrimidines derivatives or its officinal salt.Specifically; described composition includes 6 acetyl group, 8 cyclopenta 5 methyl 2 ((base of 5 (base of piperidines 4) pyridine 2) amino) pyrido [2; 3 d] (8H) ketone of pyrimidine 7 or its pharmacologically acceptable salt; and disintegrant; the disintegrant is the disintegrant without metallic element, and the composition dissolution is rapid.The pharmaceutical composition preparation technology of the present invention is simple, is more suitable for the big production of technology.
Description
The invention belongs to field of pharmaceutical preparations; more particularly to a kind of composition containing 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] (8H) -one of pyrimidine -7 or its pharmacologically acceptable salt.
Breast cancer is one of the most common malignant tumors in women, with disease incidence height, have much invasion, but disease progression is slow, Chinese population association has issued " Chinese mammary gland disease survey report " in Beijing on 2 1st, 2010, report display, the death rate of China urban area breast cancer increases 38.91%, breast cancer, which has become, threatens maximum disease to WomanHealth, at present at least 156 kinds of the breast cancer medicines for grinding and listing, wherein 68% is target therapeutic agent, numerous studies find that tumour is unusual related to the cell cycle, the mass mutation of mitogenic signals albumen and antimitotic signal protein defect lead to Proliferative Disorders in tumour cell；Simultaneously all there is genomic instability (GIN) and genome unstability (CIN) in most of tumour, these three basic cell cycle defects are all directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK, Cyclin Dependent Kinase) inhibitor has become popular target.
There are many a generation two generations CDK inhibitor developed at present, two generation drugs of greatest concern include the CDK4/6 inhibitor PD-0332991 of Pfizer company and Onyx company joint development, its activity by inhibiting CDK4/6, inhibit the phosphorylation of Rb, make the retention of E2F-Rb compound in endochylema, blocks the starting of cell cycle.Clinical test results (NCT00721409) display, progresson free survival phase (the Progression-free survival of the patient of Letrozole single therapy, PFS) it is 7.5 months, and the patient of Letrozole and the treatment of PD-0332991 drug combination then extends to 26.1 months its progresson free survival phase, this significant advantage obtains extensive concern.
WO2014183520 discloses a series of CDK4/6 inhibitor for meeting formula (I) general formula similar with PD-0332991 structure; inhibitory activity and high selectivity with significant CDK4/6; and these expected compounds are possibly used for a series of tumours; and it can be used in combination with a series of existing antitumor agents; including formula A compound as follows; its entitled 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one of chemistry:
The PCT/CN2016/070636 that applicant formerly submits describes the isethionate and its I crystal of above compound.
However above-mentioned document fails to disclose how to obtain the pharmaceutical composition of dissolution quickly and completely, meanwhile, on
It is bad to state compound stability, it is therefore desirable to which further investigation discovery dissolves out good composition, and solves stability problem.
Summary of the invention
The purpose of the present invention is to provide a kind of dissolutions rapidly, and complete pharmaceutical composition, and pharmaceutical composition preparation process is simple, is more suitable for technology mass production.On the other hand, the present invention also provides a kind of pharmaceutical compositions having good stability.
Pharmaceutical composition provided by the invention contains (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2 as active constituent; 3-d] (8H) -one of pyrimidine -7 or its pharmacologically acceptable salt and disintegrating agent, the disintegrating agent be the disintegrating agent without metallic element.Wherein the metallic element is alkali or alkaline earth metal, such as sodium, potassium, calcium, magnesium.In a preferred embodiment of the present invention, the disintegrating agent contained in composition is one of low-substituted hydroxypropyl cellulose or crospovidone or a variety of.Its content is not particularly limited, and by weight, can be about 1-30%, preferably 8%-15%.
In pharmaceutical composition provided in the present invention, the pharmacologically acceptable salt of the active constituent can preferably be selected from the isethionate of active constituent.Total weight based on composition, the content range of the active constituent can be the 5%-50% based on composition total weight agent；It is preferred that 10%-35%, more preferably 25%-35%.
In pharmaceutical composition provided in the present invention, also contain filler, the filler contains mannitol.In a preferred embodiment of the present invention, the filler except mannitol, can also contain one or more of microcrystalline cellulose, pregelatinized starch, calcium monohydrogen phosphate, preferably microcrystalline cellulose.In preferred embodiments, the filler is the mixture of mannitol and microcrystalline cellulose.
In composition of the invention, the content of filler is not particularly limited, and can be the 20-90%, preferably 30%-70%, more preferably 40%-65%, most preferably 45%-60% of the gross weight of described pharmaceutical composition.Wherein the weight ratio of mannitol and microcrystalline cellulose is 2:1 to 10:1, preferably 2.5:1 to 5:1, most preferably 2.5:1 to 3:1.In one embodiment of the invention, the ratio of mannitol and microcrystalline cellulose used is 3:1, can significantly improve the stability and dissolution rate and degree of sample.
In pharmaceutical composition provided in the present invention, adhesive can also be contained, such as adhesive is one or more of polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose, total weight based on composition, described adhesive content is about 0.5-10%, preferably 0.5%-5%.
In pharmaceutical composition provided in the present invention, pharmaceutical composition provided by the invention also may include one or more lubricants, facilitate filling capsule or tabletting.Total weight based on composition, lubricant can be selected from talcum powder, magnesium stearate, zinc stearate, Compritol 888 ATO etc..The content of lubricant is about 0.5%-5%.
In especially preferred embodiment of present invention, a kind of pharmaceutical composition is provided, contains following ingredient by weight:
1) (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one or its pharmacologically acceptable salt of 10%-35%；
2) mannitol of 20%-70%；
3) 5%-30% microcrystalline cellulose；
4) disintegrating agent of 8%-15% is selected from one or both of low-substituted hydroxypropyl cellulose or crospovidone；
5) adhesive of 0.5%-5% is selected from one or more of polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl methylcellulose；
6) the optionally lubricant of 0.5%-5% is selected from one or more of magnesium stearate, stearic acid, Compritol 888 ATO.
Pharmaceutical composition of the invention can be prepared using the common method in this field, such as the methods of bulk drug of pretreatment adds with interior granulation, dry granulation, one-step palletizing prepare medicament composition granule, are then pressed into tablet.
Composition dissolution of the invention is very quickly and completely, according to 2015 editions two the second methods of annex dissolution determination (paddle method) of Chinese Pharmacopoeia, using purified water as dissolution medium, it is preferred that the purified water of 1000ml, and dissolution test is carried out to the present composition with the paddle speed of 50rpm at 37 ± 0.5 DEG C, 40 minutes or 45 minutes dissolution rates are more than or equal to 80%, are preferably more than or equal to 95% 45 minutes or 60 minutes dissolution rates.
On the other hand, pharmaceutical composition provided by the invention improves its stability due to using the filler containing mannitol, composition of the invention is placed in the environment of 40 DEG C of temperature, relative humidity 75%, it places 1 month, is then measured using HPLC method, related content of material is no more than 1%.
Fig. 1 shows dissolution curve of the tablet of embodiment 1-5 in purified water.
Fig. 2 shows dissolution curve of the tablet of embodiment 6-9 in purified water.
Dissolution curve of the tablet of Fig. 3 display embodiment 1 and 10-12 in purified water.
Dissolution curve of the tablet of Fig. 4 display embodiment 10 and 13-14 in purified water.
By following embodiment and experimental example, present invention be described in more detail.These embodiments and experimental example being merely to illustrate property purpose, and the range being not intended to restrict the invention.
Embodiment 1-5
By 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2, 3-d] (8H) the -one isethionate of pyrimidine -7 (hereinafter referred to as compound A), lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose or crospovidone, croscarmellose sodium, sodium carboxymethyl starch, in the ratio in table 1, wet granulation is carried out using high-shearing granulation machine, 5% aqueous solution being configured to using PVP K30 is wetting agent, wet whole grain and drying process are carried out to wet softwood, then dry particl (moisture is less than 3%) is subjected to dry whole grain, the magnesium stearate of recipe quantity is added, it is uniformly mixed.Obtained total mix particle is tabletted.
Table 1
Experimental example 1: dissolution experiment
According to 2015 editions two the second methods of annex dissolution determination (paddle method) of Chinese Pharmacopoeia, dissolution determination is carried out to the tablet in Examples 1 to 5.Use the purified water of 1000ml as dissolution medium, and dissolution test is carried out with the paddle speed of 50rpm at 37 ± 0.5 DEG C.The result shows that compound A dissolution is slowly and incomplete in embodiment 2 and 3；In embodiment 4, compound A is dissolved out completely.In embodiment 5, compound A is dissolved out completely, and dissolution rate is slow compared with tablet in embodiment 1.Dissolution data are as shown in table 2 below, and dissolution curve is shown in Fig. 1
Table 2
Embodiment 6-9
By 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2, 3-d] (8H) the -one isethionate of pyrimidine -7 (hereinafter referred to as compound A), mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, in the ratio in table 3, wet granulation is carried out using high-shearing granulation machine, 3% aqueous solution being configured to using hydroxypropyl methylcellulose E5 is wetting agent, wet whole grain and drying process are carried out to wet softwood, then dry particl (moisture is less than 3%) is subjected to dry whole grain, the magnesium stearate of recipe quantity is added, it is uniformly mixed.Obtained total mix particle is tabletted.
Table 3
Experimental example 2: dissolution experiment
According to 2015 editions two the second methods of annex dissolution determination (paddle method) of Chinese Pharmacopoeia, dissolution determination is carried out to the tablet of embodiment 6~9.Use the purified water of 1000ml as dissolution medium, and dissolution test is carried out with the paddle speed of 50rpm at 37 ± 0.5 DEG C.The result shows that compound A dissolution is complete in embodiment 6~9.Dissolution data are shown in Table 4, and dissolution curve is shown in Fig. 2.
Table 4
Embodiment 10~12
By 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2, 3-d] (8H) the -one isethionate of pyrimidine -7 (hereinafter referred to as compound A), lactose or mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, in the ratio in table 5, wet granulation is carried out using high-shearing granulation machine, 5% aqueous solution being configured to using PVP K30 is wetting agent, wet whole grain and drying process are carried out to wet softwood, then dry particl (moisture is less than 3%) is subjected to dry whole grain, the magnesium stearate of recipe quantity is added, it is uniformly mixed.Obtained total mix particle is tabletted.
Table 5
Experimental example 2: dissolution experiment
According to 2015 editions two the second methods of annex dissolution determination (paddle method) of Chinese Pharmacopoeia, dissolution determination is carried out to the tablet of embodiment 1 and 10~12.Use the purified water of 1000ml as dissolution medium, and dissolution test is carried out with the paddle speed of 50rpm at 37 ± 0.5 DEG C.The result shows that compound A dissolution is complete in embodiment 1 and 10；In embodiment 11 and 12, the ratio of microcrystalline cellulose is gradually increased, and compared with the tablet in embodiment 1, the dissolution rate of compound A is gradually slack-off and dissolution is incomplete.Dissolution data are as shown in table 6 below, and dissolution curve is shown in Fig. 3.
Table 6
Embodiment 13~14
By 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2, 3-d] (8H) the -one isethionate of pyrimidine -7 (hereinafter referred to as compound A), mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, in the ratio in table 7, wet granulation is carried out using high-shearing granulation machine, 3% aqueous solution that 5% aqueous solution and hydroxypropyl methylcellulose E5 being configured to respectively with PVP K30 are configured to, using 13% aqueous solution that pregelatinized starch is configured to as wetting agent, wet whole grain and drying process are carried out to wet softwood, then dry particl (moisture is less than 3%) is subjected to dry whole grain, the magnesium stearate of recipe quantity is added, it is uniformly mixed.Obtained total mix particle is tabletted.
Table 7
Experimental example 4: dissolution experiment
According to 2015 editions two the second methods of annex dissolution determination (paddle method) of Chinese Pharmacopoeia, dissolution determination is carried out to the tablet of embodiment 10,13,14.Use the purified water of 1000ml as dissolution medium, and dissolution test is carried out with the paddle speed of 50rpm at 37 ± 0.5 DEG C.The result shows that compound A is dissolved out completely in embodiment 10；In embodiment 14, compound A dissolution is incomplete；In embodiment 13, compound A is dissolved out completely.Dissolution data are as shown in table 8 below, and dissolution curve is shown in Fig. 4.
Table 8
Experimental example 5: stability study
In the environment of embodiment 1,10 is placed in 40 DEG C of temperature, relative humidity 75%, 1 month, 2 months, 3 months are placed, HPLC method is then respectively adopted and measures the variation in relation to substance.
Related substance testing result shows that the starting of tablet in embodiment 1 is greater than the related substance total amount of tablet in embodiment 10 in relation to substance total amount；After tablet is placed 1 month in embodiment 1, related substance increases；Implement in 10 after tablet placement 1 month, 2 months, 3 months, related substance does not have significant change (being shown in Table 9).
Table 9
The synthesis of embodiment 15:6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one isethionate
Step 1:6- ((6- (1- vinyl butyl ether base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyrido [2,3-d] pyrimidine -2-base) amino) -5', 6'- dihydro-[3,4'- bipyridyl] -1'(2'H)-t-butyl formate preparation
Under argon gas protection, by (10g, 29.06mmol) 2- amino -6- (1- fourth oxyethylene group) -8- cyclopenta -5- picoline simultaneously [2, 3-d] pyrimidine -7 (8H) -one (being prepared by WO2014183520 published method), cesium carbonate (14.22g, 43.75mmol), 3 (2.12g of Pd2 (dba), 2.31mmol), 4, the bis- diphenylphosphines -9 of 5-, 9- xanthphos (2.69g, 4.69mmol) put into three mouthfuls of reaction flasks with 125.00g dioxane, it is heated to flowing back after mixing evenly, raw material 4- (6- chloropyridine -3- base) -5 is slowly added dropwise, 6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester (10.34g, 3 5.00mmol, be purchased from Yancheng City Rui Kang medication chemistry Co., Ltd) and dioxane (65.62g, 0.74mol) mixed liquor (time for adding about 5h).It drips Bi Jixu return stirring and reacts 1~1.5h, TLC monitors raw material 2- amino -6- (1- fourth oxyethylene group) -8- cyclopenta -5- picoline simultaneously [2,3-d] (8H) -one of pyrimidine -7 fully reacting (solvent: petroleum ether: ethyl acetate=2:1, raw material Rf=0.6, product Rf=0.7), terminate reaction.Reaction solution is cooled to room temperature, and filtering, filter cake is washed with methylene chloride 17.19g × 3.Filtrate is concentrated under reduced pressure in 65 DEG C and is done.The dissolution of 137.50g methylene chloride is added in residue, and 56.25g purified water, liquid separation is added, and water phase uses 68.75g methylene chloride to extract again.Merge organic phase, anhydrous sodium sulfate dries, filters, and filter cake is washed with 23.44g methylene chloride, and filtrate is concentrated under reduced pressure into oily liquids in 45 DEG C.150g acetone solution is added, about 2h, ice-water bath stir about 3h is stirred at room temperature.Filtering, filter cake are washed with cold acetone 25g × 4, and 8~10h of reduced pressure at room temperature obtains solid about 14.84g, yield: 80~92%, HPLC detect purity not less than 90%.ESI/MS:[M+H]=601.43.
The preparation of step 2:4- (6- ((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyrido [2,3-d] pyrimidine -2-base) amino) pyridin-3-yl) piperidines -1- t-butyl formate
By 6- ((6- (1- vinyl butyl ether base) -8- cyclopenta -5- methyl -7- carbonyl -7; 8- dihydro pyrido [2; 3-d] pyrimidine -2-base) amino) -5'; 6'- dihydro-[3; 4'- bipyridyl] -1'(2'H)-t-butyl formate (14.84g; it 24.69mmol) is put into three mouthfuls of reaction flasks with 75g acetic acid, leads to argon gas protection.It is added 10%Pd/C (5g), hydrogen is replaced three times, reacts 30~32h in 50~60 DEG C of atmospheric hydrogenations under stirring.HPLC method monitors intermediate state surplus (6- ((6- (1- vinyl butyl ether base) -8- cyclopenta -5- methyl -7- carbonyl -7,8- dihydro pyrido [2,3-d] pyrimidine -2-base) amino) -5', 6'- bis-
Hydrogen-[3,4'- bipyridyl] -1'(2'H)-t-butyl formate takes off normal-butyl protection but the intermediate that is not reduced of double bond) < 0.3%, terminate reaction.Reaction solution is cooled to room temperature, and is filtered after the displacement of system argon gas, filter cake is washed with 37.50g methylene chloride.Filtrate is concentrated to dryness in 65 DEG C.Residue argon gas protection 50g dehydrated alcohol reflux mashing 0.5h, stirs lower cooled to room temperature, ice bath stirring about 4h.Filtering, filter cake are washed with cold dehydrated alcohol 12.50g × 2.Methylene chloride 31.25g stirring is added in gained wet product, filters insoluble matter, is slowly added to isopropanol 118.75g, ice bath stirring about 3h under filtrate stirring, 8~10h is dried under reduced pressure after filtering and obtains solid about 8.75g, and yield: 60~72%, HPLC detect purity and be not less than 98%.ESI/MS:[M+H]=547.26.
The preparation of step 3:6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one isethionate
By 4- (6- ((6- acetyl group -8- cyclopenta -5- methyl -7- carbonyl -7; 8- dihydro pyrido [2; 3-d] pyrimidine -2-base) amino) pyridin-3-yl) piperidines -1- t-butyl formate (8.75g; it 15.94mmol) puts into three mouthfuls of reaction flasks, stirs evenly with 56.25g anhydrous methanol.80% isethionic acid (8.81g, 55.94mmol) and water 0.94g are dissolved in 13.75g anhydrous methanol, are added drop-wise in above-mentioned solution, solution becomes clarification.Drop, which finishes to be heated to reflux, is stirred to react 3~3.5h, and TLC detects raw material fully reacting (petroleum ether: ethyl acetate=1:1, raw material Rf=0.3, product Rf=0), terminates reaction, filters while hot.Filtrate stirring is lower to be added dropwise triethylamine (4.00g, 39.38mmol), drips Bi Jixu stir about 1h, ice bath stirring about 3h.Filtering, filter cake are washed with cold anhydrous methanol 7.19g × 2, and 40 DEG C are dried under reduced pressure 6~8h and obtain solid about 7.97g, yield: 82~93%, HPLC detect purity and are not less than 98%.
TOF-MS:[M+H]=447.2503 (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] (8H) -one of pyrimidine -7 combines a hydrionic quasi-molecular ions).
Claims (14)
- A kind of pharmaceutical composition; contain (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2 as active constituent; 3-d] (8H) -one of pyrimidine -7 or its pharmacologically acceptable salt and disintegrating agent, the disintegrating agent be the disintegrating agent without metallic element.
- Pharmaceutical composition according to claim 1, the metallic element are alkali or alkaline earth metal.
- Pharmaceutical composition according to claim 1, the disintegrating agent are one of low-substituted hydroxypropyl cellulose or crospovidone or a variety of.
- Pharmaceutical composition according to claim 1, wherein the disintegrating agent is by weight, content is about 1-30%, preferably 8%-15%.
- Pharmaceutical composition according to claim 1, also contains filler, and the filler contains mannitol.
- Pharmaceutical composition according to claim 5, the filler also contain selected from one or more of microcrystalline cellulose, pregelatinized starch, calcium monohydrogen phosphate, preferably microcrystalline cellulose.
- Pharmaceutical composition according to claim 5 or 6, the content of the filler are the 20-90%, preferably 30%-70%, more preferably 40%-65%, most preferably 45%-60% of described pharmaceutical composition gross weight.
- Pharmaceutical composition according to claim 6, wherein the weight ratio of mannitol and microcrystalline cellulose is 2:1 to 10:1, preferably 2.5:1 to 5:1, most preferably 2.5:1 to 3:1.
- Pharmaceutical composition according to claim 1, also contains adhesive, and described adhesive is selected from one or more of polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
- Pharmaceutical composition according to claim 1, also contains lubricant, and the lubricant is selected from one or more of magnesium stearate, stearic acid, Compritol 888 ATO.
- Pharmaceutical composition as claimed in any of claims 1 to 10, wherein the pharmacologically acceptable salt of the active constituent is isethionate.
- A kind of pharmaceutical composition contains following ingredient by weight:1) (6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyrido [2,3-d] pyrimidine -7 (8H) -one or its pharmacologically acceptable salt of 10%-35%；2) mannitol of 20%-70%；3) 5%-30% microcrystalline cellulose；4) disintegrating agent of 8%-15% is selected from one or both of low-substituted hydroxypropyl cellulose or crospovidone；5) adhesive of 0.5%-5% is selected from one or more of polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl methylcellulose；6) the optionally lubricant of 0.5%-5% is selected from one or more of magnesium stearate, stearic acid, Compritol 888 ATO.
- According to claim 1, the preparation method of pharmaceutical composition described in any one of -12, the method are selected from one of wet granulation, dry granulation process and direct powder compression, preferably wet granulation.
- Purposes of the pharmaceutical composition described in any one of -12 in the drug of preparation treating cancer according to claim 1；The preferred breast cancer of cancer, the breast cancer of more preferable estrogen receptor positive.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610080476 | 2016-02-04 | ||
| CN201610080476X | 2016-02-04 | ||
| PCT/CN2017/072213 WO2017133542A1 (en) | 2016-02-04 | 2017-01-23 | Pharmaceutical composition comprising pyridopyrimidine derivative or pharmaceutically acceptable salt thereof |
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| CN107405350A true CN107405350A (en) | 2017-11-28 |
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| CN (1) | CN107405350A (en) |
| HK (1) | HK1243351A1 (en) |
| TW (1) | TWI737673B (en) |
| WO (1) | WO2017133542A1 (en) |
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| CN113993505B (en) * | 2019-06-20 | 2023-12-12 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition and preparation method thereof |
| CN116981446A (en) * | 2021-03-03 | 2023-10-31 | 苏州盛迪亚生物医药有限公司 | Pharmaceutical composition containing pyridopyrimidine derivatives and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86100279A (en) * | 1985-01-19 | 1986-11-19 | 拜尔公司 | The method for preparing the Pyridopyrimidine compounds |
| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
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| WO2016169422A1 (en) * | 2015-04-22 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Crystal form of a cyclin-dependent kinase inhibitor and the preparation method thereof |
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2017
- 2017-01-23 WO PCT/CN2017/072213 patent/WO2017133542A1/en active Application Filing
- 2017-01-23 CN CN201780000891.2A patent/CN107405350A/en active Pending
- 2017-01-24 TW TW106102619A patent/TWI737673B/en active
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2018
- 2018-03-01 HK HK18102971.9A patent/HK1243351A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86100279A (en) * | 1985-01-19 | 1986-11-19 | 拜尔公司 | The method for preparing the Pyridopyrimidine compounds |
| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
Non-Patent Citations (1)
| Title |
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| 谢向阳等: "甲氧氯普胺口崩片的制备及体外溶出度考察", 《中国药师》 * |
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| WO2017133542A1 (en) | 2017-08-10 |
| TW201728329A (en) | 2017-08-16 |
| TWI737673B (en) | 2021-09-01 |
| HK1243351A1 (en) | 2018-07-13 |
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